Process to produce oxazolidinones

ABSTRACT

The present invention includes a number of novel intermediates such as the (S)-secondary alcohol of formula (VIIIA) 
     
       
         X 2 —CH 2 —C • H(OH)—CH 2 —NH—CO—R N    (VIIIA)  
       
     
     and processes for production of pharmacologically useful oxazolidinones.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. Ser. No. 10/422,334 filed Apr.24, 2003, which is a divisional of U.S. Ser. No. 10/352,533 filed Jan.28, 2003, U.S. Pat. No. 6,613,944 which is a divisional of U.S. Ser. No.10/271,861 filed Oct. 16, 2002, U.S. Pat. No. 6,563,003 which is adivisional of U.S. Ser. No. 10/047,705, filed Jan. 15, 2002, U.S. Pat.No. 6,492,555 which is a divisional of U.S. Ser. No. 09/927,007, filedAug. 9, 2001, U.S. Pat. No. 6,410,788 which is a divisional of U.S. Ser.No. 09/546,357, filed Apr. 10, 2000, U.S. Pat. No. 6,362,334 which is adivisional of U.S. Ser. No. 09/170,776, filed Oct. 13, 1998, U.S. Pat.No. 6,107,519 which claims the benefit of U.S. provisional applicationSerial No. 60/064,738, filed Nov. 7, 1997, under 35 USC §119(e)(1).

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is a process to prepare pharmacologically activeoxazolidinones and various intermediates used in the process.

2. Description of the Related Art

Various 5-acetamidomethyloxazolidinones are well known to those skilledin the art as pharmacologically useful antibactericals. Various methodsare well known to those skilled in the art for preparing these usefultherapeutic agents.

U.S. Pat. Nos. 5,164,510, 5,182,403 and 5,225,565 disclose5′-indolinyloxazolidinones, 3-(5′-indazolyl)oxazolidinones,3-(fused-ring substituted)phenyloxazolidinones respectively useful asantibacterial agents.

U.S. Pat. Nos. 5,231,188 and 5,247,090 disclose various tricyclic[6.5.5] and [6.6.5]-fused ring oxazolidinones useful as antibacterialagents.

International Publication WO93/09103 discloses mono- and di-halo phenyloxazolidinone anti-bacterials which are useful as pharmaceutical agentsfor their anti-bacterial action.

Prior art processes to make oxazolidinones involve condensation of anaromatic carbamate with a non-nitrogen caontaining three-carbon reagentto give an intermediate oxazolidinone with a hydroxymethyl substituentat the 5-position. The hydroxyl must then be replaced by an acetamidogroup to give the pharmacologically active5-acetamidomethyloxazolidinones. Many variants of this essentiallytwo-step process have been developed.

U.S. Pat. Nos. 4,150,029, 4,250,318, 4,476,136, 4,340,606 and 4,461,773disclose the synthesis of 5-hydroxymethyloxazolidinones from amines(R—NHX₁, where X₁ is —H or p-toluenesulfonyl) and R,S-glycidol(C^(#)H₂—O—C^(#)H—CH₂—OH where the carbon atoms marked^(#) are bondedtogether, cyclized to form an epoxide). The mixture of enantiomersproduced by this process (represented by the formulaR—NH—CH₂—CHOH—CH₂—OH) are separated by fractional crystallization of themandelic acid salts. The enantiomerically pure R-diol is then convertedin the corresponding 5R-hydroxymethyl substituted oxazolidinones bycondensation with diethylcarbonate in the presence of sodium methoxide.These 5R-hydroxymethyl substituted oxazolidinones must be aminated in asubsequent step.

J. Med. Chem., 32, 1673 (1989), Tetrahedron 45, 1323 (1989) and U.S.Pat. No. 4,948,801 disclose a method of producing oxazolidinones whichcomprises reacting an isocyanate (R—N═C═O) with (R)-glycidyl butyrate inthe presence of a catalytic amount of lithium bromide-tributylphosphineoxide complex to produce the corresponding 5R-butyryloxymethylsubstituted oxazolidinone. The process is performed at 135-145°. Thebutyrate ester is then hydrolyzed in a subsequent step to give thecorresponding 5R-hydroxymethyl substituted oxazolidinone. The5R-hydroxymethyl substituted oxazolidinone must then be aminated in asubsequent step.

Abstracts of Papers, 206th National Meeting of the American ChemicalSociety, Chicago, Ill., August, 1993; American Chemical Society:Washington, D.C., 1993; ORGN 089; J. Med. Chem. 39, 673 (1998); J. Med.Chem. 39, 680 (1996); International Publications WO93/09103, WO93/09103,WO95/07271 and WO93/23384; PCT applications PCT/US95/12751 andPCT/US95/10992; Abstracts of Papers, 35th Interscience Conference onAntimicrobial Agents and Chemotherapy, San Francisco, Calif., September1995; American Society for Microbiology: Washington, D.C., 1995;Abstract No. F208; Abstracts of Papers, 35th Interscience Conference onAntimicrobial Agents and Chemotherapy, San Francisco, Calif., September,1995; American Society for Microbiology: Washington, D.C., 1995;Abstract No. F207; Abstracts of Papers, 35th Interscience Conference onAntimicrobial Agents and Chemotherapy, San Francisco, Calif., September,1995; American Society for Microbiology: Washington, D.C., 1995;Abstract No. F206; Abstracts of Papers, 35th Interscience Conference onAntimicrobial Agents and Chemotherapy, San Francisco, Calif., September,1995; American Society for Microbiology: Washington, D.C., 1995;Abstract No. F227; disclose the reaction of a carbamate withn-butyllithium, lithium diisopropylamide or lithium hexamethyldisilazideat −78° to −40° followed by glycidyl butyrate at −78° followed bywarming to 20-25° to produce 5R-hydroxymethyl substituted oxazolidinoneswhere the ester is cleaved during the reaction. The 5R-hydroxymethylsubstituted oxazolidinones must then be aminated in a subsequent step.

International Publication WO95/07271 discloses the ammonolysis of5R-methylsulfonyloxymethyl substituted oxazolidinones.

U.S. Pat. No. 4,476,136 discloses a method of transforming5-hydroxymethyl substituted oxazolidinones to the corresponding5(S)-aminomethyl substituted oxazolidinones (VII) that involvestreatment with methane sulfonyl chloride followed by potassiumphthalimid followed by hydrazine.

J. Med. Chem., 32, 1673 (1989) and Tetrahedron 45, 1323 (1989) disclosea method for transforming 5-hydroxymethylsubstituted oxazolidinones intothe corresponding 5S-acetamidomethyl substituted oxazolidinones thatinvolves treatment with methanesulfonyl chloride or tosyl chloride,followed by sodium azide, followed by trimethylphosphite or platinumdioxide/hydrogen, followed by acetic anhydride or acetyl chloride togive the desired 5(S)-acetamidomethyl substituted oxazolidinone.

U.S. Pat. No. 5,837,870 discloses a process to prepare5(S)-hydroxymethyl substitued oxazolidinone intermediates which areuseful in the preparation of the pharmacologically active5(S)-acetamidomethyloxazolidinoes. It further discloses a process toconvert the 5-hydroxymethyl substitued oxazolidinone intermediates into5-aminomethyl substitued oxazolidinone intermediates which can beacylated to produce the pharmacologically active 5(S)-acetamidomethylsubstitued oxazolidinones.

J. Med. Chem., 33, 2569 (1990) discloses the condensation of anisocyanate with racemic glycidyl azide to produce a racemic5-azidomethyl-substituted oxazolidinone. Two subsequent steps arerequired to convert the racemic azidomethyl-substituted oxazolidinoneinto racemic 5-acetamidomethyl-substituted oxazolidinone, which hasantibiotic activity. The present invention converts isocyanates into the(S)-enantiomer of acetamidomethyl-substituted oxazolidinones which havegreater antibiotic activity than the racemates, in one step.

U.S. Pat. No. 5,332,754 discloses (col. 2, lines 14-34) that racemicoxazolidinone-CH₂—NH-Ac can be synthesized in one step by condensationof a carbamate with racemic glycidyl acetamide “in the presence of abase” such as an amine, “alkali metal hydroxide, an alkali metalalkoxide, and the like”, and that “it is preferred to carry out thereaction under heating . . . preferably at a temperature between 90 C.and 110° C.” (col. 4, lines 44-56). Evidence indicates that under theseconditions rearrangement to an undesired product occurs. The patentprovides no yields or description of this process in the Examples.Indeed, the EXAMPLEs disclose not a one-step process but multi-steproutes that are known to those skilled in the art involving mesylationof a 5-hydroxymethyl substituted oxazolidinone followed by azidedisplacement, hydrogenation and acetylation of the amin. In particular,see EXAMPLEs 59-63. The present invention differs in that the contactingbetween the carbamate (IX) and the epoxide (VIIIB) is performed underconditions that competing rearrangement to the undesired side productsis largely suppressed.

Tetrahedron Letters, 37, 7937-40 (1996) discloses a sequence forsynthesis of S-glycidylacetamide (R²=—NHAc) and a process forcondensation of a carbamate with 1.1 equivalents of n-butyl lithium(THF, −78°) followed by 2 equivalents of S-glycidylacetamide to give thecorresponding 5S-acetamidomethyl-substituted oxazolidinone. The presentinvention differs in that the contacting between the carbamate (IX) andS-glydidylacetamide is performed in the presence of lithium alkoxidebases or the carbamate (IX) is contacted with the S-chlorohydrinacetamide (VIIIA) or S-chloroacetate acetamide (VIIIC) or an isocyanate(XIV) is contacted with the S-chlorohydrin acetamide (VIIIA).

U.S. Pat. No. 3,654,298 discloses the synthesis of5-alkoxymethyl-3-aryl-substituted oxazolidinones by sodium ethoxideinduced cyclization of chlorocarbamates. The present invention differsin that the substituent at the 5-position is acylamino.

SUMMARY OF INVENTION

Disclosed is an (S)-secondary alcohol of formula (VIIIA), an (S)-epoxideof formula (VIIIB), an (S)-ester of formula (VIIIC), an (S)-protectedalcohol of the formula (IVA), an (S)-phthalimide alcohol of formula(IVC), an (S)-phthalimide epoxide of formula (IVD), an (S)-imine ofglydidylamine of formula (IVB), an (S)-intermediate of formula (XV) andan (S)-oxazolidinone phthalamide intermediate of formula (XVI).

Also disclosed is a process for the preparation of a (S)-3-carbon aminoalcohol of the formula (V) which comprises (1) contacting a non-nitrogenadduct of formula (I) with aqueous ammonia (II) in the presence of an(S)-protected-epoxide of formula (III) and (2) contacting the reactionmixture of step (1) with acid.

Further disclosed is a process for the preparation of an (S)-3-carbonamino alcohol of the formula (V) which comprises (1) contacting aphthalimide of formula (VI) with an (S)-protected-epoxide of formula(III) in the presence of potassium phthalamide in DMF or DMAC to give an(S)-phthalimide alcohol of formula (IVC) and (2) contacting the productof step (1) with aqueous acid.

Additionally disclosed is a process for the preparation of a secondaryalcohol of the formula (VIIIA) which comprises (1) contacting an(S)-3-carbon amino alcohol of the formula (V) with an acylating agentand a tri(alkyl)amine.

Disclosed is a process for the production of an(S)-oxazolidinone-CH₂—NH—CO—R_(N) of formula (X) which comprises (1)contacting a carbamate of formula (IX) with an oxygenated amino reagentselected from the group consisting of an (S)-secondary alcohol of thformula (VIIIA), an (S)-epoxide of the formula (VIIIB) or an (S)-esterof the formula (VIIIC) in the presence of a lithium cation and a basewhose conjugate acid has a pK_(a) of greater than about 8.

Also disclosed is a process for the production of an(S)-oxazolidinone-CH₂—NH—CO—R_(N) of formula (X) which comprises (1)contacting a carbamate of formula (IX) with a phthalimide alcohol of theformula (IVC) or a phthalimide epoxide of the formula (IVD), in thepresence of a lithium cation and a base whose conjugate acid has apK_(a) of greater than about 8, (2) contacting the product of step (1)with aqueous acid, (3) contacting the reaction mixture of step (2) withan acid anhydride of the formula O(CO—R_(N))₂ or an acid halide of theformula R_(N)—CO—X₄ and a tri(alkyl)amine where alkyl is C₁-C₅.

Further disclosed is a process for the production of an(S)-R_(oxa)-RING-CH₂—NH—CO—R_(N) of the formula (X) which comprises (1)contacting a carbamate of the formula (IX) with a compound selected fromthe group consisting of a (S)-protected alcohol of the formula (IVA) ora (S)-3-carbon protected epoxide of the formula (IVB) in the presence ofa lithium cation and a base whose conjugate acid has a pK_(a) of greaterthan about 8 to produce a (S)-protected oxazolidinone of the formula(XII), (2) contacting the reaction mixture of step (1) with aqueous acidto produce an (S)-oxazolidinone free amine of the formula (XIII) and (3)contacting the product of step (2) with an acylating agent selected fromthe group consisting of an acid anhydrid of the formula O(CO—R_(N))₂ oran acid halide of the formula R_(N)—CO—X₄ and where R_(N) is as definedabove and a tri(alkyl)amine where alkyl is C₁-C₅ where R_(oxa) is asdefined above.

Additionally disclosed is a process for the production of an(S)-R_(oxa)-RING-CH₂—NH—CO—R_(N) of the formula (X) which comprises (1)contacting a carbamate of the formula (IX) in the presence of a lithiumcation and a base whose conjugate acid has a pK_(a) of greater thanabout 8 to produce an (S)-oxazolidinone free amine of the formula(XIII), and (2) acylating the (S)-oxazolidinone free amine (XIII) withan acylating agent selected from the group consisting of an acidanhydride of the formula O(CO—R_(N))₂ or an acid halide of the formulaR_(N)—CO—X₄ and a tri(alkyl)amin where alkyl is C₁-C₅.

DETAILED DESCRIPTION OF THE INVENTION

The present invention includes both novel intermediates and processesuseful in the production of commercially valuable oxazolidinoneantibiotics (X. One of the novel processes is set forth in CHART D andis the reaction of a carbamate (IX) with either a (S)-secondary alcohol(VIIIA) or (S)-epoxide (VIIIB) or (S)-ester (VIIIC) to produce thecorresponding pharmacologically active (S)-oxazolidinone-CH₂—CO—R₁ (X).A second process to produce the pharmacologically active(S)-oxazolidinone-CH₂—CO—R₁ (X) is set forth in CHART H and involvesreaction of an isocynate (XIV) with a (S)-secondary alcohol (VIIIA) togive the (S)-intermediate (XV) which is then readily transformed to thecorresponding pharmacologically active (S)-oxazolidinone-CH₂—CO—R₁ (X).

The three carbon nitrogen containing fragments (S)-secondary alcohol(VIIIA), (S)-epoxide (VIIIB) and (S)-ester (VIIIC) can be produced intwo differet ways. This fragment produces the two adjacent carbon atomsof the oxazolidinone ring, the methylene carbon atom attached thereto aswell as the nitrogen atom attached to the methylene group. These threecarbon nitrogen containing fragments (S)-secondary alcohol (VIIIA),(S)-epoxide (VIIIB) and (S)-ester (VIIIC) are produced according to theprocesses of CHART C.

CHART A discloses a process to prepare the (S)-3-carbon amino alcohol(V) from the (S)-X₂-epoxide (III) using a non-nitrogen containing adduct(I) and ammonia (II) as the source of nitrogen. In the (S)-X₂-epoxide(III), and other compounds of this invention # indicates that the atomsmarked with a (#) are bonded to each other resulting in the formation ofa ring (epoxide). For the (S)-X₂-epoxides (III) it is preferred that X₂be —Cl. The (S)-X₂-epoxides (III) are either known to those skilled inthe art or can readily be prepared from compounds known to those skilledin the art by methods known to those skilled in the art. For thenon-nitrogen containing adduct (I) it is preferred that X₀ is φ; it ismore preferred that X₀ is φ. The reaction of the non-nitrogen adduct(I), ammonia (II) and the (S)-X₂-epoxide (III) is performed as set forthin EXAMPLEs 1 and 14. It should be noted that if one starts withenantiomerically pure (S)-X₂-epoxide (III) that one then obtainsenantiomerically pure (S)-protected alcohol (IVA). The absoluteconfiguration of the carbon atom in the pharmacologically useful(S)-oxazolidinone-CH₂—CO—R₁ (X) product is “S” and therefore it ispreferable to begin with enantiomerically pure (S)-X₂-epoxide (III) andobtain enantiomerically pure (S)-protected alcohol (IVA), see CHART A.In the CHARTS and CLAIMS the suprascripted “*” as —C*(a)(b)- denotes theasymetric carbon atom has the appropriate enantiomeric configuration(S)- such that when this carbon atom becomes part of the(S)-oxazolidinone-CH₂—CO—R₁ (X), it is the correct enantiomer. If onebegins any of the chemical sequences of the processes of the presentinvention with an optically impure (racemic) form rather than anenantiomerically pure form, it is apparent to on skilled in the art thatthe products obtained will be the corresponding optically impure(racemic) forms.

The (S)-protected alcohol (IVA) is then contacted with an acid to formthe corresponding (S)-3-carbon amin alcohol (V). Neither the nature,strength nor amount of the acid is critical. It is preferred that theacid have a pK_(a) less than 4. It is immaterial whether the acid isorganic or inorganic. The (S)-3-carbon amino alcohol becomes the cationand the nonproton portion of the acid is the anion. For example if themixture is acified with sulfuric acid the (S)-3-carbon amino alcohol (V)is obtained as the sulfate salt. The nature of the anion is notimportant.

CHART B discloses a way to prepare the desired (S)-3-carbon aminoalcohol (V) from the same (S)-X₂-epoxide (III) but using a nitrogencontaining adduct (VI). In this situation, no ammonia (II) is needed. Inthe final step of the process, where the product of step one iscontacted with aqueous acid, it is preferred that the acid behydrochloric, hydrobromic, hydroiodic, sulfuric or p-toluenesulfonicacid.

CHART C discloses the process to convert the (S)-3-carbon amino alcohol(V) to the corresponding (S)-secondary alcohol (VIIIA), (S)-epoxide(VIIIB) or (S)-ester (VIIIC) and the conversion of the (S)-secondaryalcohol (VIIIA) to the corresponding (S)-epoxide (VIIIB) and (S)-ester(VIIIC) respectively. To convert the (S)-3-carbon amino alcohol (V) tothe corresponding (S)-secondary alcohol (VIIIA) the 3-carbon aminoalcohol (5) is reacted with an appropriate acylating reagent such as anacyl halide or acyl anhydride under acylation reaction conditions wellknown to those skilled in the art, see EXAMPLE 2. It is preferred thatthe acylating reagent be selected from the group consisting of an acidanhydride of the formula O(CO—R_(N))₂ where R_(N) is C₁-C₅ alkyl or anacid halide of the formula R_(N)—CO—X₄ where X₄ is —Cl or —Br and atri(alkyl)amine where alkyl is C₁-C₅. It is more preferred that R_(N) isC₁ alkyl and X₄ is —Cl. It is more preferred that the acylating reagentbe the acyl anhydride and it is preferred that the acyl anhydride beacetic anhydride.

Alternatively, the (S)-epoxide (VIIIB) can be obtained by reaction ofthe (S)-ester (VIIIC) with bases such as sodium methoxide or potassiumcarbonate/methanol. Also the (S)-3-carbon amino alcohol (V) can betransformed to the corresponding (S)-ester (VIIIC) by reaction withacetic anhydride in pyridine, see EXAMPLE 3. The (S)-epoxide (VIIIB) canbe produced from the corresponding (S)-secondary alcohol (VIIIA) byreaction with potassium t-butoxide in THF at −20°, see EXAMPLE 11.Further the (S)-secondary alcohol (VIIIA) can be transformed to thecorresponding (S)-ester (VIIIC) by reaction with the acylating reagentsdiscussed above. For the (S)-ester (VIIIC), it is preferred that R_(N)is —CO—CH₃.

CHART D discloses the process of reacting a carbamate of the formulaR_(oxa)—NH—CO—O—CH₂—X₁ (IX) with either the (S)-secondary alcohol(VIIIA), the (S)-epoxide (VIIIB) or (S)-ester (VIIIC) to produce thecorresponding (S)-oxazolidinone-CH₂—CO—R₁ (X). The carbamate (IX) areknown to those skilled in the art or can be readily prepared from knowncompounds by methods known to those skilled in the art. It is preferredthat X₁ is —H. R_(oxa) is phenyl substituted with one —F and onesubstituted amino group. Substituted amino groups include4-(benzyloxycarbonyl)-1-piperazinyl, 4-morpholinyl and4-hydroxyacetylpiperazinyl. It is preferred that R_(oxa) is3-fluoro-4-[4-(benzyloxycarbonyl)-1-piperazinyl)phenyl or3-fluoro-4-(4-morpholinyl)phenyl. The carbamate (IX) and the threecarbon unit (VIIIA, VIIIb or VIIIC) is reacted by contacting thereactants with a base. The nature of which is not critical so long as itis strong enough to deprotonate the carbamate (IX). Operable bases arethose whose conjugate acid has a pK_(a) of greater than about 8.Preferred bases include compounds selected from the group consisting of:

alkoxy compounds of one thru seven carbon atoms,

carbonate,

methyl, sec-butyl and t-butyl carbanions,

tri(alkyl)amines where the alkyl group is from 1 thru 4 carbon atoms,

conjugate base of the carbamate (II),

DBU,

DBN,

N-methyl-piperidine,

N-methyl morpholine,

2,2,2-trichloroethoxide and

Cl₃C—CH₂—O⁻; most preferred bases are where the base is alkoxy of fouror five carbon atoms. It is preferred that the four and five carbonalcohol bases be t-amylate or t-butoxide. Sodium or potassium bases incombination with a lithium salt (such as—lithium chloride or lithiumbromide) can be used forming the lithium cation and base in situ. Thenature of the solvent is not critical. Operable solvents include cyclicethers such as THF, amides such as DMF and DMAC, amines such astriethylamine, acetonitrile, and alcohols such as t-amyl alcohol andt-butyl alcohol. The choice of solvent depends on the solubility of thecarbamate (IX) and the three carbon unit (VIIIA, VIIIb or VIIIC) as isknown to those skilled in the art.

CHART E discloses the reaction of the carbamate (IX) with either the(S)-phthalimid alcohol (IVC) or the (S)-phthalimide epoxid (IVD) toproduce the (S)-ring-phthalimide (XI) which is then converted to thecorresponding (S)-oxazolidinone-CH₂—NH—CO—R_(N) (X) product which haspharmaceutical utility.

CHART F discloses the reaction of the carbamate (IX) with either(S)-protected alcohol (IVA) or (S)-imine of glydidylamine (IVB) toproduce the corresponding (S)-oxazolidinone protected compound (XII)which is then transformed to the (S)-oxazolidinon free amine (XIII)which is then acylated as discussed above to produce the(S)-oxazolidinone-CH₂—NH—CO—R_(N) (X) product which has pharmaceuticalutility. These processes are the same as those for CHARTS D and E or arewell known to those skilled in the art.

CHART G discloses the reaction of the carbamate (IX) directly with the(S)-3-carbon amino alcohol (V) to give the (S)-oxazolidinone free amine(XIII) which is then acylated to give the(S)-oxazolidinone-CH₂—NH—CO—R_(N) (X). These processes are preformed inthe same manner as previously disclosed.

CHART H discloses the reaction of teh isocynate (XIV) with (S)-secondaryalcohol (VIIIA) to give the (S)-intermediate (XV) which is thentransformed to the (S)-oxazolidinone-CH₂—NH—CO—R_(N) (X), see EXAMPLES6, 8 and 9.

CHART I discloses a reaction analogous to that of CHART E. Whereas thprocess of CHART E used a carbamate (IX), the process of CHART I uses anisocynate (XIV).

The (S)-oxazolidinone-CH₂—CO-amines (X) are known to be useful asantibiotic pharmaceuticals.

DEFINITIONS AND CONVENTIONS

The definitions and explanations below are for the terms as usedthroughout this entire document including both the specification and theclaims.

I. CONVENTIONS FOR FORMULAS AND DEFINITIONS OF VARIABLES

The chemical formulas representing various compounds or molecularfragments in the specification and claims may contain variablesubstituents in addition to expressly defined structural features. Thesevariable substituents are identified by a letter or a letter followed bya numerical subscript, for example, “Z₁” or “R_(i)” where “i” is aninteger. These variable substituents are either monovalent or bivalent,that is, they represent a group attached to the formula by one or twochemical bonds. For example, a group Z₁ would represent a bivalentvariable if attached to the formula CH₃—C(═Z₁)H. Groups R_(i) and R_(j)would represent monovalent variable substituents if attached to theformula CH₃—CH₂—C(R_(i))(R_(j))—H. When chemical formulas are drawn in alinear fashion, such as those above, variable substituents contained inparentheses are bonded to the atom immediately to the left of thevariable substituent enclosed in parenthesis. When two or moreconsecutive variable substituents are enclosed in parentheses, each ofthe consecutive variabl substitu nts is bonded to the immediatelypreceding atom to the left which is not enclosed in parentheses. Thus,in the formula above, both R_(i) and R_(j) are bonded to the precedingcarbon atom. Also, for any molecule with an established system of carbonatom numbering, such as steroids, these carbon atoms are designated asC_(i), where “i” is the integer corresponding to the carbon atom number.For example, C₈ represents the 6 position or carbon atom number in thesteroid nucleus as traditionally designated by those skilled in the artof steroid chemistry. Likewise the term “R₆” represents a variablesubstituent (either monovalent or bivalent) at the C₆ position.

Chemical formulas or portions thereof drawn in a linear fashionrepresent atoms in a linear chain. The symbol “—” in general representsa bond between two atoms in the chain. Thus CH₃—O—CH₂—CH(R_(i))—CH₃represents a 2-substituted-1-methoxypropane compound. In a similarfashion, the symbol “═” represents a double bond, e.g.,CH₂═C(R_(i))—O—CH₃, and the symbol “≡” represents a triple bond, e.g.,HC≡C—CH(R_(i))—CH₂—CH₃. Carbonyl groups are represented in either one oftwo ways: —CO— or —C(═O)—, with the former being preferred forsimplicity.

Chemical formulas of cyclic (ring) compounds or molecular fragments canbe represented in a linear fashion. Thus, the compound4-chloro-2-methylpyridin can be represented in linear fashion byN^(#)═C(CH₃)—CH═CCl—CH═C^(#)H with the convention that the atoms markedwith an asterisk (#) are bonded to each other resulting in the formationof a ring. Likewise, the cyclic molecular fragment,4-(ethyl)-1-piperazinyl can be represented by—N^(#)—(CH₂)₂—N(C₂H₅)—CH₂—C^(#)H₂.

A rigid cyclic (ring) structure for any compounds herein defines anorientation with respect to the plane of the ring for substituentsattached to each carbon atom of the rigid cyclic compound. For saturatedcompounds which have two substituents attached to a carbon atom which ispart of a cyclic system, —C(X₁)(X₂)— the two substituents may be ineither an axial or equatorial position relative to the ring and maychange between axial/equatorial. However, the position of the twosubstituents relative to the ring and each other remains fixed. Whileeither substituent at times may lie in the plane of the ring(equatorial) rather than above or below the plane (axial), onesubstituent is always above the other. In chemical structural formulasdepicting such compounds, a substituent (X₁) which is “below” anothersubstituent (X₂) will be identified as being in the alpha (α)configuration and is identified by a broken, dashed or dotted lineattachment to the carbon atom, i.e., by the symbol “- - -” or “ . . . ”.The corresponding substituent attached “above” (X₂) the other (X₁) isidentified as being in the beta (β) configuration and is indicated by anunbroken lin attachment to th carbon atom.

When a variable substituent is bivalent, the valences may be takentogether or separately r both in the definition of the variable. Forexample, a variable R_(i) attached to a carbon atom as —C(═R_(i))— mightbe bivalent and be defined as oxo or keto (thus forming a carbonyl group(—CO—) or as two separately attached monovalent variable substituentsα-R_(i-j) and β-R_(i-k). When a bivalent variable, R_(i), is defined toconsist of two monovalent variable substituents, the convention used todefin the bivalent variable is of the form “α-R_(i-j):β-R_(i-k)” or somevariant thereof. In such a case both α-R_(i-j) and β-R_(i-k) areattached to the carbon atom to give —C(α-R_(i-j))(β-R_(i-k))—. Forexample, when the bivalent variable R₆, —C(═R₆)— is defined to consistof two monovalent variable substituents, the two monovalent variablesubstituents are α-R₆₋₁:β-R₆₋₂, . . . α-R₆₋₉:β-R₆₋₁₀, etc, giving—C(α-R₆₋₁)(β-R₆₋₂)—, . . . —C(α-R₆₋₉)(β-R₆₋₁₀)—, etc. Likewise, for thebivalent variable R₁₁, —C(═R₁₁)—, two monovalent variable substituentsare α-R₁₁₋₁:β-R₁₁₋₂. For a ring substituent for which separate α and βorientations do not exist (e.g. due to the presence of a carbon carbondouble bond in the ring), and for a substituent bonded to a carbon atomwhich is not part of a ring the above convention is still used, but theα and β designations are omitted.

Just as a bivalent variable may be defined as two separate monovalentvariable substituents, two separate monovalent variable substituents maybe defined to be taken together to form a bivalent variable. Forexample, in the formula —C₁(R_(i))H—C₂(R_(j))H— (C₁ and C₂ definearbitrarily a first and second carbon atom, respectively) R_(i) andR_(j) may be defined to be taken together to form (1) a second bondbetween C₁ and C₂ or (2) a bivalent group such as oxa (—O—) and theformula thereby describes an epoxide. When R_(i) and R_(j) are takentogether to form a more complex entity, such as the group —X—Y—, thenthe orientation of the entity is such that C₁ in the above formula isbonded to X and C₂ is bonded to Y. Thus, by convention the designation“. . . R_(i) and R_(j) are taken together to form —CH₂—CH₂—O—CO— . . . ”means a lactone in which the carbonyl is bonded to C₂. However, whendesignated “ . . . R_(j) and R_(i) are taken together to form—CO—O—CH₂—CH₂—the convention means a lactone in which the carbonyl isbonded to C₁.

The carbon atom content of variable substituents is indicated in one oftwo ways. The first method uses a prefix to the entire name of thevariable such as “C₁-C₄”, where both “1” and “4” are integersrepresenting the minimum and maximum number of carbon atoms in thevariable. The prefix is separated from the variabl by a space. Forexample, “C₁-C₄ alkyl” represents alkyl of 1 through 4 carbon atoms,(including isomeric forms thereof unless an express indication to thecontrary is given). Wh never this single prefix is given, the prefixindicates the entire carbon atom content of the variable being defined.Thus C₂-C₄ alkoxycarbonyl describes a group CH₃—(CH₂)_(n)—O—CO— where nis zero, one or two. By the second method th carbon atom content of onlyeach portion of the definition is indicated separately by enclosing the“C_(i)-C_(j)” designation in parentheses and placing it immediately (nointervening space) before the portion of the definition being defined.By this optional convention (C₁-C₃)alkoxycarbonyl has the same meaningas C₂-C₄ alkoxycarbonyl because the “C₁-C₃” refers only to the carbonatom content of the alkoxy group. Similarly while both C₂-C₆ alkoxyalkyland (C₁-C₃)alkoxy(C₁-C₃)alkyl define alkoxyalkyl groups containing from2 to 6 carbon atoms, the two definitions differ since the formerdefinition allows either the alkoxy or alkyl portion alone to contain 4or 5 carbon atoms while the latter definition limits either of thesegroups to 3 carbon atoms.

When the claims contain a fairly complex (cyclic) substituent, at theend of the phrase naming/designating that particular substituent will bea notation in (parentheses) which will correspond to the samename/designation in one of the CHARTS which will also set forth thechemical structural formula of that particular substituent.

II. DEFINITIONS

All temperatures are in degrees Centigrade.

TLC refers to thin-layer chromatography.

HPLC refers to high pressure liquid chromatography.

THF refers to tetrahydrofuran.

* indicates that the carbon atom is an enantiomeric carbon in the (S)configuration

# indicates that the atoms marked with a (#) are bonded to each otherresulting in the formation of a ring.

RING is defined in CHART J as the oxazolidinone ring, a2,5-disubstituted-oxazolidinone.

DMF refers to dimethylformamide.

DMAC refers to dimethylacetamide.

Chromatography (column and flash chromatography) refers topurification/separation of compounds expressed as (support, eluent). Itis understood that the appropriate fractions are pooled and concentratedto give the desired compound(s).

IR refers to infrared spectroscopy.

CMR refers to C-13 magnetic resonance spectroscopy, chemical shifts arereported in ppm (δ) downfield from TMS.

NMR refers to nuclear (proton) magnetic resonance spectroscopy, chemicalshifts are reported in ppm (δ) d wnfield from tetram thylsilane.

TMS refers to trimethylsilyl.

-φ refers to phenyl (C₆H₅).

[α]_(D) ²⁵ refers to the angle of rotation of plane polarized light(specific optical rotation) at 25° with the sodium D line (589A).

MS refers to mass spectrometry expressed as m/e, m/z or mass/chargeunit. [M+H]⁺ refers to the positive ion of a parent plus a hydrogenatom. EI refers to electron impact. CI refers to chemical ionization.FAB refers to fast atom bombardment.

Pharmaceutically acceptable refers to those properties and/or substanceswhich are acceptable to the patient from a pharmacological/toxicologicalpoint of view and to the manufacturing pharmaceutical chemist from aphysical/chemical point of view regarding composition, formulation,stability, patient acceptance and bioavailability.

When solvent pairs are used, the ratios of solvents used arevolume/volume (v/v).

When the solubility of a solid in a solvent is used the ratio of thesolid to th solvent is weight/volume (wt/v).

EXAMPLES

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, practice the present invention toits fullest extent. The following detailed examples describe how toprepare the various compounds and/or perform the various processes ofthe invention and are to be construed as merely illustrative, and notlimitations of the preceding disclosure in any way whatsoever. Thoseskilled in the art will promptly recognize appropriate variations fromthe procedures both as to reactants and as to reaction conditions andtechniques.

PREPARATION 1 3-Fluoro-4-morpholinylaniline

3,4-Difluoronitrobenzene (25.196 g, 158.38 mmol) is added to a mixtureof morpholine (60.0 ml, 688 mmol, 4.34 eq) in THF (30 ml) at −14°. Themixture is permitted to warm to 10° then maintained at 10-13° for 1 hr.A mixture of citric acid monohydrate (75 g, 357 mmol, 2.25 eq) in water(365 ml) is added with concomitant exotherm to 28°. The phases areseparated and th aqueous phase is washed with toluene (95 ml). Theorganic phase is washed with water (315 ml) and concentrated underreduced pressure. Toluene (46 ml) and methanol (60 ml) are addedfollowed by palladium on Carbon (5%, 50% water wet, 3.1603 g, 0.7426mmol, 0.00469 eq) and the mixture sealed in a Parr shaker. Hydrogenpressure (40 psi) is applied and maintained while agitating for 42 min.The catalyst is then removed by filtration under reduced pressure andwashed with toluene (60 ml). Heptane (150 ml) is added to the filtrateand the resultant slurry concentrated under reduced pressure. Heptane(300 ml) is added and the precipitate collected by filtration underreduced pressure and washed with heptane and dried to give the titlecompound, HPLC (stationary phase is 4.6×250 mm zorbax RX C-8 column;mobile phase is acetonitrile (650 ml), triethylamine (1.85 ml) andacetic acid (1.30 ml) and water of sufficient amount to make 1,000 ml;flow rate=3.0 ml/min; UV detection at 254 nm) RT=1.08 min, >99.3 area);NMR (Pyridine-D₅) 2.95-2.98, 3.80-3.83, 5.38, 6.68, 6.78 and 6.90 δ; CMR(Pyridine-D₅) 52.43, 67.33, 103.31, 110.63, 121.29, 130.80, 146.23 and157.72 δ.

PREPARATION 2 N-Carbomethoxy-3-fluoro-4-morpholinylaniline (IX)

3,4-Difluoronitrobenzene (PREPARATION 1, 24.967 g, 158.94 mmol) is addedto a mixture of morpholine (60.0 ml, 688 mmol, 4.38 eq) in THF (30 ml)at −6°. Th mixture is permitted to warm to 10° over 2 hrs thenmaintained at 10° for ½ hr. A mixture of citric acid monohydrate (75 g,357 mmol, 2.27 eq) in water (365 ml) is added with concomitant exothermto 28°. The phases are separated and the aqueous washed with toluene (95ml). The organic phases are washed with water (315 ml), the aqueous backwash extracted with toluene (95 ml) and concentrated under reducedpressure. Toluene (76 ml) and methanol (60 ml) are added followed bypalladium on carbon (5%, 50% water wet, 3.1370 g, 0.7371 mmol, 0.00470eq) and the mixture sealed in a Parr shaker. Hydrogen pressure (40 PSI)is applied and maintained while agitating for 4.5 hrs. The catalyst isthen removed by filtration under reduced pressure and washed withtoluene (100 ml). The mixture is cooled to 2° and a mixture of aqueouspotassium carbonate (47%, 17.1 ml, 85 mmol, 0.54 eq) and water (150 ml)is added. Methyl chloroformate (16.4 ml, 212 mmol, 1.35 eq) is thenadded while maintaining the temperature at about 3-3.5°. The resultantslurry is permitted to warm to 20-25° and stirred 17 hrs. The mixture iswarmed to 75° to give a solution, then cooled to 46°, heptane (333 ml)added, then the mixture cooled to 0°, the precipitate collected byfiltration with reduced pressure, washed with heptane (100 ml cooled to5°) then water (230 ml cooled to 5°) and dried to give th titlecompound, TLC (silica gel; methanol/methylene chloride, 5/95) R_(f)=0.74(on spot); NMR (CDCl₃) 3.03, 3.76, 3.86, 6.75, 6.87, 6.98, 7.27; CMR(CDCl₃) 51.18, 52.4, 67.03, 107.81, 114.58, 119.00, 133.25, 135.77,154.07, 155.70.

PREPARATION 3 3-Fluoro-4-morpholinylphenylisocyanate (XIV)

A mixture of 3-Fluoro-4-morpholinylaniline (PREPARATION 1, 12.01 g,61.21 mmol) in methylene chloride (100 ml) is added to a mixture ofphosgene (1.93 M in toluene, 63.4 ml, 122.4 mmol, 2.00 eq) inp-chlorotoluene (60 ml) over 15 min, a while maintaining the temperaturefrom about −12 to 3°. The material is rinsed in with methylene chloride(30 ml). The mixture is then warmed to 130° under atmospheric pressurewith concomitant distillation of methylene chloride, phosgene, tolueneand hydrogen chloride gas into a caustic scrubber. The mixture is cooledto 25° and filtered. The precipitate is washed with methylene chloride(3×15 ml). The filtrate is concentrated under reduced pressure. Heptane(200 ml) is added to the concentrated filtrate and the resultant slurrycooled to −32°. The product is collected by filtration with reducedpressure, washed with heptane cooled to −30°, and dried in a nitrogenstream to give the title compound, HPLC (stationary phase is 4.6×250 mmzorbax RX C-8 column; mobile phase is acetonitrile (650 ml),triethylamine (1.85 ml) and acetic acid (1.30 ml) and water ofsufficient amount to make 1,000 ml; flow rate=3.0 ml/min; UV detectionat 254 nm) RT=1.08 min. Upon derivatizing asN-carbomethoxy-3-fluoro-4-morpholinylaniline by dissolving in methanol;NMR (CDCl₃) 3.05, 3.86 and 6.78-6.89 δ; CMR (CDCl₃) 50.90, 66.89,113.11, 119.15, 120.83, 124.67, 127.65, 138.06 and 155.40 δ; MS (EI) m/z(relative intensity 222 (37) and 164 (100).

Example 1 (S)-1-Amino-3-chloro-2-propanol Hydrochloride (V)

(S)-Epichlorohydrin (III, 44.978 g, 486.1 mmol, 98.9% enantiomericexcess, 99.3 chemical % purity) is added to a mixture of benzaldehyde(I, 50.0 ml, 492 mmol, 1.012 eq), ethanol (163 ml) and aqueous ammonia(II, 29.8 wt %, 50 ml, 787.4 mmol, 1.62 eq) at 18° over 10 min with anexotherm to 22°. The reaction mixture is permitted to exotherm to 34°over 1.5 hrs, warmed to 42°, stirred at 20-25° for 20.5 hrs, then warmedto 74° and immediately allowed to cool. The mixture is concentratedunder reduced pressure to give (S)-1-benzalimino-3-chloro-2-propanol(IVA). Water (382 ml) and hydrochloric acid (37.7 wt %, 76.2 ml, 938mmol, 1.93 eq) is added to the concentrate and the mixture stirred at20-25° for 2 hrs. Toluene (150 ml) is added and the phases areseparated. The organic phase is washed with water (15 ml) and thecombined aqueous washed with toluene (2×150 ml), back extracting eachorganic extract with water (15 ml). The combined aqueous extracts areconcentrated under reduced pressure. Ethanol (200 ml) is added to theconcentrate and the mixture concentrated under reduced pressure. Ethanol(300 ml) is added to the concentrate and the mixture warmed to reflux.The mixture is cooled to −30° and the precipitate collected byfiltration with reduced pressure, washed with −30° ethanol (2×60 ml) anddried in a nitrogen stream to give a white solid, mp=132-141°; NMR(CD₃OD) 2.96, 3.21, 3.57-3.64 and 4.03-4.09 δ; CMR (CD₃OD) 43.52, 46.91and 68.72 δ; MS (CI, NH₃), M/Z (relative intensity) 129 (24), 127 (69),112 (61), 110 (100); [α]²⁵ _(D)=−22 (c=1.00, H₂O).

Example 2 (S)-1-Acetamido-2-hydroxy-3-chloropropane (VIIIA)

Triethylamine (10.5 ml, 75.3 mmol, 1.11 eq) is added to a slurry of(S)-1-amino-3-chloro-2-propanol hydrochloride (V, EXAMPLE 1, 9.938 g,68.059 mmol) in THF (80 ml) at −40° and the mixture stirred for 5 min at−40°. Acetic anhydride (6.78 ml, 71.86 mmol, 1.056 eq) is then added at−40° and the mixture allowed to warm to 20-25° over 1.5 hrs. Theprecipitate is removed by filtration with reduced pressure and washedwith THF. The filtrate is treated with magnesol (5.69 g), which isremoved by filtration with reduced pressure and washed with THF (2×60ml). The filtrate is then concentrated under reduced pressure. Theconcentrate is purified by flash chromatography (silica gel; elutingwith a gradient of 75-100% ethyl acetate/cyclohexane) to give the titlecompound, NMR (CDCl₃) 2.03, 3.32, 3.50-3.57, 3.55, 3.91-4.13, 5.01 and7.09 δ; CMR (CDCl₃) 28.00, 43.31, 46.52, 70.65 and 172.40 δ; MS (CI,NH₃), M/Z (relative intensity), 171 (41.6), 169 (100), 154 (22.4), 152(48.1); [α]²⁶ _(D)=7.44 (c=1.00, H₂O).

Example 3 (±)-1-Acetamido-2-acetoxy-3-chloropropane (VIIIC)

Acetic anhydride (18 ml) is added to a thin slurry of(±)-1-amino-3-chloro-2-propanol hydrochloride ((±)-V, EXAMPLE 5, 5.0110g, 34.317 mmol) in pyridine (20 ml) while maintaining the temperature inthe range of 20-50°. The mixture is stirred at 20-25° for 18 hours, thenwater (14 ml) is added with an exotherm to 65°. The mixture isconcentrated under reduced pressure and water (50 ml) is added. The pHis adjusted to 0.89 with hydrochloric acid (37.7%, 1.467 g, 15.17 mmol,0.442 eq) at 0°. The mixture is extracted with methylene chloride (4×50ml), the extracts dried over sodium sulfate and concentrated underreduced pressure. Ethyl acetate (20 ml) and heptane (20 ml) are added,the mixture seeded, then heptane (40 ml) is added to the resultantslurry. The precipitate is collected by filtration with reducedpressure, washed with heptane and dried to give a the title compound,mp=68.0-69.5°; TLC (silica gel; ethyl acetate, iodine char) R_(f)=0.39(one spot); NMR 2.00, 2.21, 3.52, 3.62, 3.70, 5.10 and 6.33 δ; CMR20.93, 23.10, 40.47, 43.53, 71.95, 170.45 and 170.71 δ; MS (CI, NH₃) m/z(relative intensity) 213 (36), 211 (100), 196 (18) and 194 (53).

Example 4 (S)-1-Phthalimido-3-chloro-2-propanol (S)-(IVC)

(S)-epichlorohydrin (III, 98.9% enantiomerically pure, 99.3 chemical %purity, 4.9605 g, 53.61 mmol) is added to a slurry of potassiumphthalimide (VI, 5.031 g, 27.161 mmol, 0.507 eq) and phthalimide (VI,11.836 g, 80.45 mmol, 1.5006 eq) in DMF (32 ml) and the mixture stirredat 50° for 4.5 hrs. The mixture is added to methylene chloride (50 ml)and water (50 ml) added. The solids are removed by filtration withreduced pressure and washed with methylene chloride (20 ml). Th phasesare separated in the filtrate and the aqueous washed with methylenchloride (50 ml). The combined organics were washed with water (50 ml)and th aqueous backextraceted with methylene chloride (50 ml) afteradding water (25 ml). The combined organics are dried over sodiumsulfate and saturated with hydrogen chloride gas at 6°. Water (100 ml)is added and the phases separated. The aqueous phase is washed withmethylene chloride (2×50 ml) and the combined organic phases are driedover sodium sulfate. The organic phase is concentrated under reducedpressure and toluene added (77 ml). The mixture is concentrated underreduced pressure to 31 g net weight and toluene (50 ml) and heptane (75ml) added. The solids are filtered off and washed with toluene/heptane(1/1, 20 ml). The filtrate is concentrated under reduced pressure to 17g net weight, heptane (100 ml) added and the mixture concentrated underreduced pressure to 15 g net weight. Heptan (100 ml) and methylenechloride (100 ml) is added and the mixture concentrated under reducedpressure to 130 g net weight. The solids are filtered out and washedwith heptane/methylene chloride (2/1, 3×15 ml). The filtrate isconcentrated under reduced pressure to 11 g net weight and toluene (90ml) then heptane (400 ml) added. The resultant slurry is then cooled to−20° and the product collected by filtration with reduced pressure,washed with heptane and dried to give a crud solid. Flash chromatographyof the crude solid (silica gel; eluting with a gradient of 15-45% ethylacetate/cyclohexane) gives the title compound as an analytical sampl,NMR 3.11, 3.62, 3.68, 3.87, 3.95, 4.14-4.20, 7.70-7.76 and 7.82-7.88 δ;CMR 41.61, 47.27, 69.68, 123.53, 131.83, 134.26 and 168.65 δ; MS (CI,NH₃), M/Z (relative intensity) 259 (1.4), 257 (17), 242 (0.11), 240(0.31), 221 (100); [α]²⁵ _(D)=−33 (C=0.712, CHCl₃). NMR of the mosherester derivative showed the product to have an enantiomeric purity of96.2% upon comparison to the NMR of the mosher ester of the racemate.

Example 5 (±)-1-Amino-3-chloro-2-propanol hydrochloride (±)-(V)

A slurry of (±)-1-phthalimido-3-chloro-2-propanol (IVC, 40.018 g, 166.98mmol) in hydrochloric acid (37.5 wt %, 79 ml, 968 mmol, 5.80 eq) andwater (82 ml) is stirred at 109° for 5 hrs. The mixture is cooled to 22°and the precipitate is removed by filtration with reduced pressure andwashed with water (40 ml). The filtrate is concentrated under reducedpressure to 26 g net weight and ethanol (100 ml) added. The mixture iswarmed to 75° to give a solution then cooled to −12° and the resultantprecipitate collected by filtration with reduced pressure, washed withethanol cooled to −12° and dried to give the title compound,mp=101-104°; NMR (CD₃OD) 2.96, 3.21, 3.57-3.64 and 4.03-4.09 δ; CMR(CD₃OD) 43.54, 46.95 and 68.71 δ; MS (CI, NH₃), M/Z (relative intensity)129 (12), 127 (39), 112 (56), 110 (100).

Example 6(S)-N-Carbo(1′-acetamido-3′-chloro-2′-propoxy)-3-fluoro-4-morpholinylaniline((S)-XV)

Acetyl chloride (0.3297 g, 4.20 mmol, 1.019 eq) is added to a slurry of(S)-1-Amino-3-chloro-2-propanol hydrochloride (V, EXAMPLE 1, 0.6020 g,4.12 mmol) and triethylamine (1.26 ml, 9.04 mmol, 2.19 eq) inacetonitrile (70 ml) at −40°.

The mixture is then warmed to 3-6°, stirred several hours, warmed to 22°and 3-fluoro-4-morpholinylphenylisocyanate (XIV, PREPARATION 8, 1.0152g, 4.568 mmol, 1.108 eq) added. The mixture is warmed to 64°, stirred 10min, then concentrated under reduced pressure to about 25 ml.3-Fluoro-4-morpholinylphenylisocyanate (XIV, 0.0907 g, 0.408 mmol,0.09887 eq) is then added and the mixture stirred at 65° for 17 hours.Pentanol (1.34 ml, 12.33 mmol, 2.99 eq) is added and the mixture stirredat 65° for 1.7 hrs. Water (5 ml) is added and the mixture cooled to −4°.Water (38 ml) and heptane (30 ml) were added and the mixture warmed to15° and stirred 1 hr. The resulting precipitate is collected byfiltration under reduced pressureand washed with heptane and water anddried to give a solid. The filtrate is concentrated under reducedpressure to 50 ml total volume and the precipitate collected byfiltration under reduced pressure, washed with water (10 ml) and heptane(10 ml) and dried to give a brown solid. A portion of the first solids(0.9404 g) and the second solids (0.4018 g) is dissolved in acetonitrile(15 ml) at 76°, then cooled to −10° and the precipitate collected byfiltration under reduced pressure, washed with acetonitrile cooled to−10° and dried to give th title compound, HPLC (stationary phase is4.6×250 mm zorbax RX C-8 column; mobile phase is acetonitrile (650 ml),triethylamine (1.85 ml) and acetic acid (1.30 ml) and water of sufficint amount to make 1,000 ml; flow rate=3.0 ml/min; UV detection at 254nm)=92.3 area %).

Example 7(S)-N-Carbo(1′-acetamido-3′-chloro-2′-propoxy)-3-fluoro-4-morpholinylaniline((S)-XV)

A mixture of (S)-1-acetamido-3-chloro-2-propanol (VIIIA, EXAMPLE 2,1.024 g, 6.754 mmol, 1.00 eq) and 3-fluoro-4-morpholinylphenylisocynate(XIV, PREPARATION 3, 1.6756 g, 7.539 mmol, 1.12 eq) in acetonitrile (25ml) is stirred at 60° for 46 hrs. The resultant slurry is cooled to−13°, the precipitate collected by filtration with reduced pressure,washed with acetonitrile cooled to −13° C. (20 ml) and dried to give thetitle compound, NMR (DMSO-D6) 1.83, 2.93, 3.2-3.5, 3.73, 3.78, 3.88,4.99, 6.97, 7.20, 7.36, 8.07 and 9.80 δ; CMR (DMSO-D6) 22.42, 39.6,44.71, 50.77, 68.15, 71.81, 106.49, 114.23, 119.21, 134.18, 134.59,152.57, 154.65 and 169.67 δ; MS (CI, NH₃), M/Z (relative intensity) 376(27.0), 374 (85.9), 339 (12.2), 338 (80.8) and 223 (17.2); [α]²⁵_(D)=−4.08 (C=0.930, DMF).

Example 8(S)-N-[[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide((S)-X)

A solution of sodium t-butoxide (0.0854 g, 0.889 mmol, 1.05 eq) inethanol (0.60 ml) is added to a slurry of(S)-N-carbo(1′-acetamido-3′-chloro-2′-propoxy)-3-fluoro-4-morpholinylaniline((S)-(XV), EXAMPLE 7, 0.3176 g, 0.850 mmol) in ethanol (4.6 ml) at 65°and is rinced in with ethanol (0.50 ml). The mixture is stirred 28 minand cooled to 0°. Citric acid monohydrate (0.1943 g, 0.925 mmol, 1.09eq) is added and the resulting slurry concentrated under reducedpressure to 1.30 g net weight. Water (10 ml) and methylene chloride (10ml) is added, the phases separated and the aqueous phase washed withmethylene chloride (2×10 ml). The combined organic phases are dried oversodium sulfate and concentrated under reduced pressure to a solid. Thesolid is dissolved in ethyl acetate (8.4 ml) at 70°, solution cooled to50°, seeded, further cooled to −28°, the precipitate collected byfiltration with reduced pressure, washed with ethyl acetate previouslycooled to −30° and dried to give the title compound, HPLC (100.7 wt %,99.9 area %, NMR (CDCl₃) 2.04, 3.04, 3.65, 3.77, 3.86, 4.02, 4.74-4.82,6.80, 6.91, 7.06 and 7.42 δ; CMR (CDCl₃) 22.99, 41.88, 47.64, 50.96,66.94, 72.08, 107.55, 113.98, 118.83, 132.93, 136.55, 154.55, 155.44 and171.40 δ; MS (EI) M/Z (relative intensity) 337 (16.9), 293 (74.4), 234(37.5), 209 (100); [α]²⁵ _(D)=−15.8 (C=0.903, ethanol).

Example 9(S)-N-[[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide(IV)

Following the general procedure of EXAMPLE 8 and making non-criticalvariations the title compound is obtained, NMR 2.02, 3.04, 3.65, 3.77,3.86, 4.02, 4.74-4.82, 6.74, 6.91, 7.06 and 7.42 δ; CMR 23.02, 41.89,47.65, 50.97, 66.87, 72.06, 107.48, 114.01, 118.76, 132.85, 136.48,154.52, 155.38 and 171.34 δ; MS (CI, NH₃), M/Z (relative intensity) 338(100), 294 (86.8); [α]²⁵ _(D)=−15.2 (C=0.783, ethanol).

Example 10 (±)-N-(2-Hydroxy-3-chloro)acetamide (VIIIA)

To a slurry of (±)-1-Amino-3-chloro-2-propanol hydrochloride (V, EXAMPLE5, 47.71 g, 3.674 mmol) in THF (381 ml) at −40° is added triethylamine(36.496 g, 360.67 mmol, 1.104 eq) followed by acetic anhydride (35.007g, 342.90 mmol, 1.049 eq) while maintaining the temperature at <−30°.The mixture is stirred 15 min at −30°, then allowed to warm to 20° over1 hr. The mixture is stirred at 20-25° for 3 hours, then the precipitateis removed by vacuum filtration through a medium frit and washed withTHF (175 ml). The filtrate is concentrated under reduced pressure to andtoluene (195 ml) added. The mixture is concentrated under reducedpressure to and toluene (250 ml) is added. The mixture is concentratedunder reduced pressure and toluene (250 ml), methanol (40 ml) and ethylacetate (10 ml) added. The mixture is cooled to −20°, seeded, heptane(200 ml) added at −30°, the mixture cooled to −33° and the precipitatecollected by vacuum filtration, washed with heptane (100 ml) and dried.This solid (44.818 g) is dissolved in toluene (250 ml) and methanol (120ml) and concentrated under reduced pressure. The mixture is cooled to−30°, seeded and heptane (180 ml) is added the precipitate collected byvacuum filtration at −30°, washed with heptane (100 ml) and dried togive a solid, mp=50.1-52.3°; TLC (silica gel; methanol/methylenechloride (5/95), iodine char) R_(f)=0.23 (single more polar spotidentified as 1.1 wt % triethylammonium acetate by NMR); NMR (CDCl₃)2.03, 3.33, 3.54, 3.95, 4.73 and 6.93 δ; CMR (CDCl₃) 23.01, 43.32,46.48, 70.72 and 172.37 δ; MS (CI, NH₃) m/z (relative intensity) 154(34), 152 (100).

Example 11 (±)-Glycidylacetamide (VIIIB)

To a solution of (±) 1-acetamido-3-chloro-2-propanol (V, EXAMPLE 10,10.344 g, 68.24 mmol) in tetrahydrofuran (21 ml) at −40° Is added asolution of potassium t-butoxide in THF (1.0 M, 65 ml, 65 mmol, 0.95eq). The mixture was warmed to −20° and stirred for 15 min then cooledto −37° and silica gel (18.5 g) is added. The solids are removed byvacuum filtration and washed with ethyl acetate (1,000 ml). Th filtrateis concentrated and the precipitate removed by vacuum filtration. Thefiltrate is concentrated and heptane (50 ml) is added. The mixture isseeded, sonicated, and the precipitate collected by vacuum filtration,washed with heptan and dried in a nitrogen stream to give the titlecompound, mp=34.6-37.3°; TLC (silica gel; methanol/methylene chloride(5/95), iodine char) R_(f)=0.24; NMR 2.01, 2.59, 2.80, 3.10-3.13,3.24-3.29, 3.7-3.9, 6.19 δ; CMR 23.07, 40.67, 45.19, 50.61 and 170.54 δ.

Example 12(±)-N-[[3-(3-Fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]acetamide(X)

To a solution of (±)-glycidylacetamide (VIIIB, EXAMPLE 11, 0.1571 g,1.365 mmol) in THF (1.63 ml) at −78° is addedN-carbomethoxy-3-fluoro-4-morpholinylaniline (IX, PREPARATION 2, 0.4358g, 1.71 mmol, 1.26 eq) and lithium t-butoxide (0.1267 g, 1.583 mmol,1.16 eq). The reaction mixture is then stirred at 0 to 11° for 17.5 hrsat which point HPLC showes an 80% yield of(±)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]acetamide(retention time=0.97 min; method B; Stationary phase: 4.6×250 mm ZorbaxRX C-8 column; mobile phase: 650 ml acetonitrile, 1.85 ml triethylamine,1.30 ml acetic acid, water sufficient to make 1000 ml; flow rate: 3.0ml/min; UV detection at 254 nm). The title compound is isolated by meansknown to those skilled in the art.

Example 13(S)-N-[[3-(3-Fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]acetamide(X)

Step A: (S)-N-(2-Hydroxy-3-chloro)acetamide (VIIIA)

Following the general procedure of EXAMPLE 10 and making non-criticalvariations but starting with (S)-1-amino-3-chloro-2-propanolhydrochloride (V, EXAMPLE 1), the title compound is obtained.

Step B: (S)-Glycidylacetamide (VIIIB)

Following the general procedure of EXAMPLE 11 and making non-criticalvariations but starting with (S)-N-(2-Hydroxy-3-chloro)acetamide (VIIIA,Step A), the title compound is obtained.

Step C:(S)-N-[[3-(3-Fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]acetamide(X)

Following the general procedure of EXAMPLE 12 and making non-criticalvariations but starting with (S)-Glycidylacetamide (VIIIB, Step B), thetitle compound is obtained.

Example 14 (S)-1-Acetamido-2-acetoxy-3-chloropropane (VIIIC)

Following the general procedure of EXAMPLE 3 and making non-criticalvariations but starting with (S)-1-Amino-3-chloro-2-propanolhydrochloride (V, EXAMPLE 1), the title compound is obtained.

Example 15 (S)-1-Amino-3-chloro-2-propanol hydrochloride (S)-(V)

Following the general procedure of EXAMPLE 5 and making non-criticalvariations but using (S)-1-phthalimido-3-chloro-2-propanol (S)-(IVC,EXAMPLE 4) th title compound is obtained.

What is claimed is:
 1. A process for the production of an(S)-R_(oxa)-RING-CH₂—NH—CO—R_(N) of the formula (X)R_(oxa)-RING-CH₂—NH—CO—R_(N)   (X) where: (I) R_(N) is C₁-C₅ alkyl; (II)R_(oxa) is phenyl substituted with one -F and one substituted aminogroup which comprises: (III) RING means

(1) contacting a carbamate of the formula (IX) R_(oxa)-NH—CO—O—CH₂—X₁  (IX) where: (1) X₁ is: (A) C₁-C₂₀ alkyl, (B) C₃-C₇ cycloalkyl, (C)φ-optionally substituted with one or two: (1) C₁-C₃ alkyl, (2) F-, Cl-,Br-, 1-, (D) CH₂═CH—CH₂—, (E) CH₃—CH═CH—CH₂—, (F) (CH₃)₂C═CH—CH₂—, (G)CH₂═CH—, (H) φ-CH═CH—CH₂—, (I) φ-CH₂-optionally substituted on φ- withone or two —Cl, C₁-C₄ alkyl, —NO₂, —CN, —CF₃, (J) 9-fluorenylmethyl, (K)(Cl)₃C—CH₂—, (L) 2-trimethylsilylethyl, (M) φ-CH₂—CH₂—, (N) 1-adamantyl,(O) (φ)₂CH—, (P) CH≡C—C(CH₃)₂— (Q) 2-furanylmethyl, (R) isobornyl, (S)—H; (II) R_(oxa) is as defined above, and (III) X₂ is (A) —Cl, (B) —Br,(C) p-CH₃-φ-SO₂—, (D) m-NO₂-φ-SO₂, with an (S)-3-carbon amino alcohol(V) in the presence of a lithium cation and a base whose conjugate acidhas a pK, of greater than about 8 to produce an (S)-oxazolidinone freeamine of the formula (XIII) R_(oxa)-RING-CH₂—NH₂   (XIII) where R_(oxa)is as defined above, and (2) acylating the (S)-oxazolidinone free amine(XIII) with an acylating agent selected from the group consisting of anacid anhydride of the formula O(CO—R_(N))₂ where R_(N) is as definedabove or an acid halide of the formula R_(N)—CO—X₄ is —Cl or —Br andwhere R_(N) is as defined above and a tri(alkyl)amine where alkyl isC₁-C₅.
 2. A process for the production of an(S)-R_(oxa)-RING-CH₂—NH—CO—R_(N) (X) according to claim 1 where R_(oxa)is: 3-fluoro-4-[4-(benzyloxycarbonyl)-1-piperazinyl]phenyl,3-fluoro-4-(4-morpholinyl)phenyl and3-fluoro-4-(4-hydroxyacetylpiperaziny)lphenyl.
 3. A process for theproduction of an (S)-R_(oxa)-RING-CH₂—NH—CO—R_(N) (X) according to claim1 where R_(N) is C₁ alkyl.
 4. A process for the production of an(S)-R_(oxa)-RING-CH₂—NH—CO—R_(N) (X) according to claim 1 where X₁ is—H.
 5. A process for the production of an(S)-R_(oxa)-RING-CH₂—NH—CO—R_(N) (X) according to claim 1 where X₂ is—Cl.